Use of cannabinoids in the treatment of epilepsy

ABSTRACT

The present disclosure relates to the use of cannabidiol (CBD) in the treatment of absence seizures. In particular, the disclosure relates to the use of CBD for reducing absence seizures in patients suffering with etiologies that include: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; CDKL5; Dup15q; Jeavons syndrome; Myoclonic Absence Epilepsy; Neuronal ceroid lipofuscinoses (NCL) and brain abnormalities. The disclosure further relates to the use of CBD in combination with one or more anti-epileptic drugs (AEDs).

FIELD OF THE INVENTION

The present invention relates to the use of cannabidiol (CBD) in thetreatment of absence seizures. In one embodiment the patients sufferingfrom absence seizures are children and young adults. CBD appearsparticularly effective in reducing absence seizures in patientssuffering with etiologies that include: Lennox-Gastaut Syndrome;Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; CDKL5;Dup15q; Jeavons syndrome; Myoclonic Absence Epilepsy; Neuronal ceroidlipofuscinoses (NCL) and brain abnormalities in comparison to otherseizure types.

Significantly CBD proved very effective in treating a sub-type ofabsence seizures, namely myoclonic absence seizures. The etiologies ofpatients which suffer from myoclonic absence seizures include DooseSyndrome, Jeavons syndrome and Myoclonic Absence Epilepsy syndrome.

In these patients treatment with CBD reduced the occurrence of absenceseizures or myoclonic absence seizures by greater than 50% in a largeproportion of patients, 64% and 75% respectively. This was surprisinggiven that the proportion of patients benefiting from a greater than 50%reduction in total seizures was significantly less, (46%), in allsubjects treated.

Preferably the CBD used is in the form of a highly purified extract ofcannabis such that the CBD is present at greater than 98% of the totalextract (w/w) and the other components of the extract are characterised.In particular the cannabinoid tetrahydrocannabinol (THC) has beensubstantially removed, to a level of not more than 0.15% (w/w) and thepropyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts ofup to 1%. Alternatively, the CBD may be a synthetically produced CBD.

In use the CBD may be used concomitantly with one or more otheranti-epileptic drugs (AED). When used in combination with another AEDthe CBD may be formulated for administration separately, sequentially orsimultaneously with the one or more AED or the combination may beprovided in a single dosage form. Where the CBD is formulated foradministration separately, sequentially or simultaneously it may beprovided as a kit or together with instructions to administer the one ormore components in the manner indicated. It may also be used as the solemedication, i.e. as a monotherapy.

BACKGROUND TO THE INVENTION

Epilepsy occurs in approximately 1% of the population worldwide,(Thurman et al., 2011) of which 70% are able to adequately control theirsymptoms with the available existing anti-epileptic drugs (AED).However, 30% of this patient group, (Eadie et al., 2012), are unable toobtain seizure freedom from the AED that are available and as such aretermed as suffering from intractable or “treatment-resistant epilepsy”(TRE).

Intractable or treatment-resistant epilepsy was defined in 2009 by theInternational League Against Epilepsy (ILAE) as “failure of adequatetrials of two tolerated and appropriately chosen and used AED schedules(whether as monotherapies or in combination) to achieve sustainedseizure freedom” (Kwan et al., 2009).

Individuals who develop epilepsy during the first few years of life areoften difficult to treat and as such are often termedtreatment-resistant. Children who undergo frequent seizures in childhoodare often left with neurological damage which can cause cognitive,behavioral and motor delays.

Childhood epilepsy is a relatively common neurological disorder inchildren and young adults with a prevalence of approximately 700 per100,000. This is twice the number of epileptic adults per population.

When a child or young adult presents with a seizure, investigations arenormally undertaken in order to investigate the cause. Childhoodepilepsy can be caused by many different syndromes and genetic mutationsand as such diagnosis for these children may take some time.

The main symptom of epilepsy is repeated seizures. In order to determinethe type of epilepsy or the epileptic syndrome that a patient issuffering from, an investigation into the type of seizures that thepatient is experiencing is undertaken. Clinical observations andelectroencephalography (EEG) tests are conducted and the type(s) ofseizures are classified according to the ILAE classification describedbelow and in FIG. 1.

The International classification of seizure types proposed by the ILAEwas adopted in 1981 and a revised proposal was published by the ILAE in2010 and has not yet superseded the 1981 classification. FIG. 1 isadapted from the 2010 proposal for revised terminology and includes theproposed changes to replace the terminology of partial with focal. Inaddition the term “simple partial seizure” has been replaced by the term“focal seizure where awareness/responsiveness is not impaired” and theterm “complex partial seizure” has been replaced by the term “focalseizure where awareness/consciousness is impaired”.

From FIG. 1 it can be seen that Generalised seizures, where the seizurearises within and rapidly engages bilaterally distributed networks, canbe split into six subtypes: Tonic-Clonic (grand mal) seizures; Absence(petit mal) Seizures; Clonic Seizures; Tonic Seizures; Atonic Seizuresand Myoclonic Seizures.

Focal (partial) seizures where the seizure originates within networkslimited to only one hemisphere, are also split into sub-categories. Herethe seizure is characterized according to one or more features of theseizure, including aura, motor, autonomic and awareness/responsiveness.Where a seizure begins as a localized seizure and rapidly evolves to bedistributed within bilateral networks this seizure is known as aBilateral convulsive seizure, which is the proposed terminology toreplace Secondary Generalised Seizures (generalized seizures that haveevolved from focal seizures and are no longer remain localized).

Absence seizures can occur as Typical absence seizures; Atypical absenceseizures or Absence seizures with special features such as Myoclonicabsence and Eyelid myoclonia.

Typical absence seizures are generalized seizures with a sudden onsetand offset of altered awareness. The altered awareness can vary inseverity dependent on the specific syndrome that the patient issuffering from. Clonic movements of the eyelids, head, eyebrows, chinperioral or other facial parts can occur, whereas myoclonus of limbsonly occurs rarely. In addition, absence status epilepticus can alsooccur.

Atypical absence seizures have a less sudden onset and offset of loss ofawareness than occurs in typical absence seizures. They are associateswith other features such as loss of muscle tone of the head, trunk orlimbs and subtle myoclonic jerks. A loss of awareness is usuallyminimal.

Myoclonic absence seizures present with bilateral rhythmic myoclonicjerks of the shoulders and arms. There is tonic abduction which resultsin progressive lifting of the arms during the seizure. Seizures lastbetween 10 and 60 seconds and there may be a complete loss of awareness.

Eyelid myoclonia are absence seizures which are accompanied by briefrepetitive myoclonic jerks of the eyelids with simultaneous upwarddeviation of the eyeballs and extension of the head. Seizures aretypically brief and multiple seizures can occur on a daily basis.Awareness is mostly retained.

Absence seizures may occur in epilepsy syndromes including:Lennox-Gastaut Syndrome; Myoclonic Absence Epilepsy; Tuberous SclerosisComplex; Dravet Syndrome; Doose Syndrome; CDKL5; Dup15q; JeavonsSyndrome; Myoclonic Absence Epilepsy; Neuronal ceroid lipofuscinoses(NCL) and brain abnormalities.

Epileptic syndromes often present with many different types of seizureand identifying the types of seizure that a patient is suffering from isimportant as many of the standard AED's are targeted to treat or areonly effective against a given seizure type/sub-type.

The first line treatment for absence seizures usually comprises a broadspectrum AED, such as sodium valproate, lamotrigine or ethosuximide. Acombination of these medicaments may be required in order to treatabsence seizures.

Common AED defined by their mechanisms of action are described in thefollowing tables:

TABLE 1 Examples of narrow spectrum AED Narrow- spectrum AED MechanismIndication Phenytoin Sodium channel Complex partial Tonic-clonicPhenobarbital GABA/Calcium channel Partial seizures Tonic-clonicCarbamazepine Sodium channel Partial seizures Tonic-clonic Mixedseizures Oxcarbazepine Sodium channel Partial seizures Tonic-clonicMixed seizures Gabapentin Calcium channel Partial seizures Mixedseizures Pregabalin Calcium channel Adjunct therapy for partial seizureswith or without secondary generalisation Lacosamide Sodium channelAdjunct therapy for partial seizures Vigabatrin GABA Secondarilygeneralized tonic- clonic seizures Partial seizures Infantile spasms dueto West syndrome

TABLE 2 Examples of broad spectrum AED Broad- spectrum AED MechanismIndication Valproic acid GABA/Sodium channel First-line treatment fortonic- clonic seizures, absence seizures and myoclonic seizuresSecond-line treatment for partial seizures and infantile spasms.Intravenous use in status epilepticus Lamotrigine Sodium channel Partialseizures Tonic-clonic Seizures associated with Lennox-Gastaut syndromeEthosuximide Calcium channel Absence seizures Topiramate GABA/Sodiumchannel Seizures associated with Lennox-Gastaut syndrome ZonisamideGABA/Calcium/Sodium Adjunctive therapy in adults channel withpartial-onset seizures Infantile spasm Mixed seizure Lennox-Gastautsyndrome Myoclonic Generalised tonic-clonic seizure LevetiracetamCalcium channel Partial seizures Adjunctive therapy for partial,myoclonic and tonic-clonic seizures Clonazepam GABA Typical and atypicalabsences Infantile myoclonic Myoclonic seizures Akinetic seizuresRufinamide Sodium channel Adjunctive treatment of partial seizuresassociated with Lennox-Gastaut syndrome

TABLE 3 Examples of AED used specifically in childhood epilepsy AEDMechanism Indication Clobazam GABA Adjunctive therapy in complex partialseizures Status epilepticus Myoclonic Myoclonic-absent Simple partialComplex partial Absence seizures Lennox-Gastaut syndrome StiripentolGABA Severe myoclonic epilepsy in infancy (Dravet syndrome)

From these tables it can be seen that the three AED that are used asfirst line treatments for absence seizures, namely: sodium valproate,lamotrigine or ethosuximide are GABA/sodium channel, sodium channel andcalcium channel drugs respectively.

It can also be seen from these tables that other AED are approved foruse in absence seizures, these include clonazepam and clobazam, both ofwhich work by a GABA mechanism.

Over the past forty years there have been a number of animal studies onthe use of the non-psychoactive cannabinoid cannabidiol (CBD) to treatseizures. For example, Consroe et al., (1982) determined that CBD wasable to prevent seizures in mice after administration of pro-convulsantdrugs or an electric current.

Studies in epileptic adults have also occurred in the past forty yearswith CBD. Cunha et al. reported that administration of CBD to eightadult patients with generalized epilepsy resulted in a marked reductionof seizures in 4 of the patients (Cunha et al., 1980).

A study in 1978 provided 200 mg/day of pure CBD to four adult patients,two of the four patients became seizure free, whereas in the remainderseizure frequency was unchanged (Mechoulam and Carlini, 1978).

In contrast to the studies described above, an open label study reportedthat 200 mg/day of pure CBD was ineffective in controlling seizures intwelve institutionalized adult patients (Ames and Cridland, 1986).

Based on the fact that chronologically the last study to look at theeffectiveness of CBD in patients with epilepsy proved that CBD wasunable to control seizures, there would be no expectation that CBD mightbe useful as an anti-convulsant agent.

In the past forty years of research there have been over thirty drugsapproved for the treatment of epilepsy none of which are cannabinoids.Indeed, there appears to have been a prejudice against cannabinoids,possibly due to the scheduled nature of these compounds and/or the factthat THC, which is a known psychoactive, has been ascribed as apro-convulsant (Consroe et al., 1977).

A paper published recently suggested that cannabidiol-enriched cannabismay be efficacious in the treatment of epilepsy. Porter and Jacobson(2013) report on a parent survey conducted via a Facebook group whichexplored the use of cannabis which was enriched with CBD in childrenwith treatment-resistant epilepsy. It was found that sixteen of the 19parents surveyed reported an improvement in their child's epilepsy. Thechildren surveyed for this paper were all taking cannabis that waspurported to contain CBD in a high concentration although the amount ofCBD present and the other constituents including THC were not known formany of the cases. Indeed, whilst CBD levels ranged from 0.5 to 28.6mg/kg/day (in those extracts tested), THC levels as high as 0.8mg/kg/day were reported.

Providing children with TRE with a cannabis extract that comprises THC,which has been described as a pro-convulsant (Consroe et al., 1977), ata potentially psychoactive dose of 0.8 mg/kg/day, is a concern and assuch there is a need to determine whether CBD is in fact efficacious.

In November 2013 the company GW Pharmaceuticals made a press release tostate that they were intending to treat Dravet Syndrome with CBD as ithad received orphan drug designation.

To date there have been no controlled trials of CBD in children andyoung adults with intractable epilepsy.

BRIEF SUMMARY OF THE DISCLOSURE

In accordance with a first aspect of the present invention there isprovided cannabidiol (CBD) for use in the treatment of epilepsy, whereinthe epilepsy is characterised by absence seizures.

In one embodiment the epilepsy is a childhood epilepsy.

In one embodiment the absence seizures are myoclonic absence seizures.

Surprisingly, the CBD has been shown to be particularly effective insubjects with epilepsy which is treatment-resistant.

In a further embodiment the CBD is for use in combination with one ormore concomitant anti-epileptic drugs (AED).

Preferably the absence seizures to be treated are in patients diagnosedwith: Lennox-Gastaut Syndrome; Myoclonic Absence Epilepsy; TuberousSclerosis Complex; Dravet Syndrome; Doose Syndrome; Jeavons Syndrome;CDKL5; Dup15q; Neuronal ceroid lipofuscinoses (NCL) and brainabnormalities.

Most preferably the treatment-resistant epilepsy is one of:Lennox-Gastaut Syndrome; Dravet Syndrome and Myoclonic Absence Epilepsy.

In a further embodiment the CBD is present as a highly purified extractof cannabis which comprises at least 98% (w/w) CBD. Preferably theextract comprises less than 0.15% THC. More preferably the extractfurther comprises up to 1% CBDV.

In an alternative embodiment the CBD is present as a synthetic compound.

In a further embodiment of the invention the one or more AED is selectedfrom the group consisting of: clobazam, clonazepam, clorazepate,desmethylclobazam, diazepam, ethosuximide, felbamate, gabapentin,ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam,midazolam, N-desmethylclobazam, nordiazepam, phenytoin, stiripentol,topiramate, trazodone, vagus nerve stimulation, valproic acid,vigabatrin, and zonisamide.

Preferably the one or more AED is selected from the group consisting ofsodium valproate; lamotrigine; ethosuximide; clobazam and clonazepam.

Preferably the number of different anti-epileptic drugs that are used incombination with the CBD is reduced. Alternatively the dose ofanti-epileptic drugs that are used in combination with the CBD isreduced.

There are many side effects associated with the commonly used AED whichinclude dizziness, blurred vision, nausea, respiratory systemdepression, tiredness, headaches, and other motor side effects on thecentral nervous system. These side effects are particularly common ashigher doses or combinations of numerous AED are used. As such there isa need for an alternative medication that is able to reduce the numbersof seizures whilst at the same time exhibiting a safe side effectprofile.

Preferably the dose of CBD is greater than 5 mg/kg/day. Thus for a 15 kgpatient a dose of greater than 75 mg of CBD per day would be provided.Doses greater than 5 mg/kg/day such as greater than 10/mg/kg/day,greater than 15 mg/kg/day, greater than 20 mg/kg/day and greater than 25mg/kg/day are also envisaged to be effective.

Preferably the epilepsy is childhood epilepsy.

In accordance with a second aspect of the present invention there isprovided a method of treating epilepsy comprising administeringcannabidiol (CBD) to a subject, wherein the epilepsy is characterised byabsence seizures.

Preferably the subject is a human, typically a patient that is sufferingfrom epilepsy characterised by absence seizures.

In accordance with a third aspect of the present invention there isprovided a composition for use in the treatment of epilepsycharacterised by absence seizures comprising cannabidiol (CBD), asolvent, a co-solvent, a sweetener, and a flavouring.

Preferably the solvent is sesame oil, the co-solvent is ethanol, thesweetener is sucralose, the flavouring is strawberry flavour and the CBDis present at a concentration of between 25/mg/ml and 100 mg/ml, namely50 mg/ml and 75 mg/ml.

More preferably the composition comprises cannabidiol (CBD) at aconcentration of between 25 to 100 mg/ml, ethanol at a concentration of79 mg/ml, sucralose at a concentration of 0.5 mg/ml, strawberryflavouring at a concentration of 0.2 mg/ml and sesame oil q.s. to 1.0ml.

It is envisaged that the composition be administered as an oral liquidsolution. Other modes of administration including solids, semi-solids,gels, sprays, aerosols, inhalers, vaporisers, enemas and suppositoriesare alternative administration forms. Such medicaments could beadministered via the oral, buccal, sublingual, respiratory, nasal anddistal rectum route.

DEFINITIONS

Definitions of some of the terms used to describe the invention aredetailed below:

The cannabinoids described in the present application are listed belowalong with their standard abbreviations.

TABLE 4 Cannabinoids and their abbreviations CBD Cannabidiol

CBDA Cannabidiolic acid

CBDV Cannabidivarin

CBDVA Cannabidivarinic acid

THC Tetrahydrocannabinol

The table above is not exhaustive and merely details the cannabinoidswhich are identified in the present application for reference. So farover 60 different cannabinoids have been identified and thesecannabinoids can be split into different groups as follows:Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (whichmay be novel cannabinoids or synthetically produced phytocannabinoids orendocannabinoids).

“Phytocannabinoids” are cannabinoids that originate from nature and canbe found in the cannabis plant. The phytocannabinoids can be isolatedfrom plants to produce a highly purified extract or can be reproducedsynthetically.

“Highly purified cannabinoid extracts” are defined as cannabinoids thathave been extracted from the cannabis plant and purified to the extentthat other cannabinoids and non-cannabinoid components that areco-extracted with the cannabinoids have been substantially removed, suchthat the highly purified cannabinoid is greater than or equal to 98%(w/w) pure.

“Synthetic cannabinoids” are compounds that have a cannabinoid orcannabinoid-like structure and are manufactured using chemical meansrather than by the plant.

Phytocannabinoids can be obtained as either the neutral (decarboxylatedform) or the carboxylic acid form depending on the method used toextract the cannabinoids. For example it is known that heating thecarboxylic acid form will cause most of the carboxylic acid form todecarboxylate into the neutral form.

“Treatment-resistant epilepsy” (TRE) or “intractable epilepsy” isdefined as per the ILAE guidance of 2009 as epilepsy that is notadequately controlled by trials of one or more AED.

“Childhood epilepsy” refers to the many different syndromes and geneticmutations that can occur to cause epilepsy in childhood. Examples ofsome of these are as follows: Dravet Syndrome; Myoclonic-AbsenceEpilepsy; Lennox-Gastaut syndrome; Generalized Epilepsy of unknownorigin; CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria;Dup15q; SNAP25; and febrile infection related epilepsy syndrome (FIRES);benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm(West syndrome); and Landau-Kleffner syndrome. The list above isnon-exhaustive as many different childhood epilepsies exist.

“Absence Seizures” are defined as a generalised type of epilepticseizure which causes a loss of awareness often accompanied by myoclonicjerks.

“Myoclonic Absence Seizures” are defined as a sub-type of absenceseizures which present with bilateral myoclonic jerks of the arms andshoulders.

“Mixed seizures” are defined as the existence of both generalised andfocal seizures in the same patient.

The terms “50% responder” and “50% reduction in seizure” are both termsused in clinical studies. In the present application the terms definethe percentage of subjects that experienced a greater than or equal to50% reduction in the number of seizures during treatment with CBD incomparison to the number experienced during the baseline period beforethe CBD was administered.

DETAILED DESCRIPTION Preparation of Highly Purified Cbd Extract

The following describes the production of the highly-purified (>98% w/w)cannabidiol extract which has a known and constant composition which wasused for the expanded access trials described in the Examples below.

In summary the drug substance used in the trials is a liquid carbondioxide extract of high-CBD containing chemotypes of Cannabis sativa L.which had been further purified by a solvent crystallization method toyield CBD. The crystallisation process specifically removes othercannabinoids and plant components to yield greater than 98% CBD.

The Cannabis sativa L. plants are grown, harvested, and processed toproduce a botanical extract (intermediate) and then purified bycrystallization to yield the CBD (drug substance).

The plant starting material is referred to as Botanical Raw Material(BRM); the botanical extract is the intermediate; and the activepharmaceutical ingredient (API) is CBD, the drug substance.

Both the botanical starting material and the botanical extract arecontrolled by specifications. The drug substance specification isdescribed in Table 5 below.

TABLE 5 CBD Specification Test Test Method Limits Appearance VisualOff-white/pale yellow crystals Identification A HPLC-UV Retention timeof major peak corresponds to certified CBD Reference StandardIdentification B GC-FID/MS Retention time and mass spectrum of majorpeak corresponds to certified CBD Reference Standard Identification CFT-IR Conforms to reference spectrum for certified CBD ReferenceStandard Identification D Melting 65-67° C. Point Identification ESpecific Conforms with certified CBD Optical Reference Standard; −110°to Rotation −140° (in 95% ethanol) Total Purity Calculation ≧98.0%Chromatographic Purity HPLC-UV ≧98.0% 1 Chromatographic Purity GC-FID/MS≧98.0% 2 Other Cannabinoids: HPLC-UV CBDA NMT 0.15% w/w CBDV NMT 1.0%w/w Δ⁹ THC NMT 0.15% w/w CBD-C4 NMT 0.5% w/w Residual Solvents: GCAlkane NMT 0.5% w/w Ethanol NMT 0.5% w/w Residual Water Karl Fischer NMT1.0% w/w NMT—Not more than

The purity of the CBD drug substance achieved is greater than 98%. Theother cannabinoids which may occur in the extract are: CBDA, CBDV,CBD-C4 and THC.

Distinct chemotypes of Cannabis sativa L. plant have been produced tomaximize the output of the specific chemical constituents, thecannabinoids. One type of plant produces predominantly CBD. Only the(−)-trans isomer occurs naturally. Furthermore during purification thestereochemistry of CBD is not affected.

Production of the Intermediate

An overview of the steps to produce a botanical extract, theintermediate, are as follows:

1. Growing 2. Decarboxylation

3. Extraction No. 1-using liquid CO₂4. Extraction No. 2-‘winterization’ using ethanol

5. Filtration 6. Evaporation

High CBD chemovars were grown, harvested and dried and stored in a dryroom until required. The botanical raw material (BRM) was finely choppedusing an Apex mill fitted with a 1 mm screen. The milled BRM was storedin a freezer for up to 3 months prior to extraction.

Decarboxylation of CBDA to CBD was carried out using a large Heraeustray oven. The decarboxylation batch size in the Heraeus isapproximately 15 Kg. Trays were placed in the oven and heated to 105°C.; the BRM took 96.25 minutes to reach 105° C. Held at 105° C. for 15Minutes. Oven then set to 150° C.; the BRM took 75.7 minutes to reach150° C.; BRM held at 150° C. for 130 Minutes. Total time in the oven was380 Minutes, including 45 minutes cooling and 15 Minutes venting.

Extraction No 1 was performed using liquid CO₂ at 60 bar/10° C. toproduce botanical drug substance (BDS).

The crude CBD BDS was winterised in Extraction No 2 under standardconditions (2 volumes of ethanol at minus 20° C. for around 50 hours).The precipitated waxes were removed by filtration and the solventevaporated using the rotary evaporator (water bath up to 60° C.) toyield the BDS, which was then used for crystallisation to produce thetest material.

Production of the Drug Substance

The manufacturing steps to produce the drug substance from theintermediate botanical extract are as follows:

1. Crystallization using C5-C12 straight chain or branched alkane

2. Filtration

3. Optional recrystallization from C5-C12 straight chain or branchedalkane4. Vacuum drying

Intermediate botanical extract (12 kg) produced using the methodologyabove was dispersed in C5-C12 straight chain or branched alkane (9000ml, 0.75 vols) in a 30 litre stainless steel vessel.

The mixture was manually agitated to break up any lumps and the sealedcontainer then placed in a freezer for approximately 48 hours.

The crystals were isolated by vacuum filtration, washed with aliquots ofcold C5-C12 straight chain or branched alkane (total 12000 ml), anddried under a vacuum of <10 mb at a temperature of 60° C. until drybefore submitting the drug substance for analysis.

The dried product was stored in a freezer at minus 20° C. in apharmaceutical grade stainless steel container, with FDA food gradeapproved silicone seal and clamps.

Production of the Drug Product

The drug product is presented as an oral solution. The oral solutionpresentation contains 25 mg/ml or 100 mg/ml CBD, with the excipientssesame oil, ethanol, sweetener and flavouring. Two product strengths areavailable to allow dose titration across a wide dose range.

The 25 mg/ml solution is appropriate at lower doses and the 100 mg/mlsolution at higher doses.

The drug product formulation is as described in Table 6 below:

TABLE 6 Drug Product specification Reference Qualitative to QualityComponent Composition Function Standard Cannabidiol (CBD) 25 mg/ml or100 mg/ml Active In-house Anhydrous ethanol 79.0 mg/ml* Excipient Ph.Eur. Sucralose 0.5 mg/ml Sweetener In-house Strawberry 0.2 mg/mlFlavouring In-house flavouring Sesame oil q.s to 1.0 ml Excipient Ph.Eur.

The drug substance, CBD is insoluble in water. Sesame oil was selectedas an excipient to solubilize the drug substance.

A sweetener and fruit flavouring are required to improve palatability ofthe sesame oil solution.

Ethanol was required to solubilize the sweetener and the flavouring.

The composition can be substantially equivalent, by which is meant thefunctional ingredients can vary from the qualitative compositionspecified in Table 6 by an amount of up to 10%.

Example 1 below describes the use of a highly purified cannabis extractcomprising cannabidiol (CBD). Cannabidiol is the most abundantnon-psychoactive cannabinoid in the selected chemovar. Previous studiesin animals have demonstrated that CBD has anticonvulsant efficacy inmultiple species and models.

Example 1 describes data produced in an expanded access treatmentprogram in children with TRE.

Example 1 Efficacy of Cannabidiol Reducing Absence Seizures in Childrenand Young Adults with Intractable Epilepsy Materials and Methods

Of 137 children and young adults with severe, childhood onsettreatment-resistant epilepsy (TRE), forty-two suffered from epilepsythat was characterised by absence seizures. These subjects were testedwith a highly purified extract of cannabidiol (CBD) obtained from acannabis plant. All subjects presented with absence type seizures, oftenin addition to other generalised and/or focal seizures. The participantsin the study were part of an expanded access compassionate use programfor CBD.

The epileptic syndromes that these patients suffered from were asfollows: Lennox-Gastaut Syndrome; Myoclonic Absence Epilepsy; TuberousSclerosis Complex; Dravet Syndrome; Doose Syndrome; Jeavons Syndrome;CDKL5; Dup15q; Neuronal ceroid lipofuscinoses (NCL) and brainabnormalities.

Seizure types experienced by these patients included: tonic, clonic,tonic-clonic, myoclonic, atonic, absence, myoclonic-absence, focalseizures without impairment, focal seizures with impairment and focalseizures evolving to bilateral convulsive seizures.

All patients entered a baseline period of 4 weeks whenparents/caregivers kept prospective seizure diaries, noting allcountable seizure types.

The patients then received a highly purified CBD extract (greater than98% CBD w/w) in sesame oil, of known and constant composition, at a doseof 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED)regimen.

The daily dose was gradually increased by 2 to 5 mg/kg increments untilintolerance occurred or a maximum dose of 25 mg/kg/day was achieved.

Patients were seen at regular intervals of 2-4 weeks. Laboratory testingfor hematologic, liver, kidney function, and concomitant AED levels wasperformed at baseline, and after every 4 weeks of CBD therapy.

The patients on the study were all taking at least one concomitant AED.These included clobazam, clonazepam, clorazepate, desmethylclobazam,diazepam, ethosuximide, felbamate, gabapentin, ketogenic diet,lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam,N-desmethylclobazam, nordiazepam, phenytoin, stiripentol, topiramate,trazodone, vagus nerve stimulation, valproic acid, vigabatrin, andzonisamide.

Results

Of the 42 children and young adult patients who received treatment withCBD, there were 28 patients who received treatment for at least 12 weeksof treatment all of whom suffered from absence type seizures.

A summary of the 50% responders, based on 12 weeks of treatment aresummarized in Table 7 below.

TABLE 7 Summary of 50% responders after 12 weeks of treatment Absenceseizures Total seizures (n = 28) (n = 137) >50% reduction in 64% (n =18) 46% (n = 63) seizures <50% reduction in 36% (n = 10) 54% (n = 74)seizures

Table 7 shows that after 3 months of therapy, a remarkable 64% ofpatients had an equal to or greater than >50% reduction in absenceseizures, these data infer that the CBD is very effective at reducingthis type of seizure.

Conclusions

These data indicate that CBD significantly reduces the number of absencetype seizures in a high proportion of patients that do not respond wellto existing AED.

It was surprising that in this group of patients which aretreatment-resistant such a high number were able to gain an effect. Thefact that nearly two thirds of the patients (64%) benefitted from atleast a fifty percent reduction in the number of absence seizures thatthey suffered from was remarkable.

Example 2 Efficacy of Cannabidiol Reducing Myoclonic Absence Seizures inChildren and Young Adults with Intractable Epilepsy Materials andMethods

Of 137 children and young adults with severe, childhood onsettreatment-resistant epilepsy (TRE), ten suffered from epilepsy that wascharacterised by myoclonic absence seizures. These subjects were testedwith a highly purified extract of cannabidiol (CBD) obtained from acannabis plant. All subjects presented with myoclonic absence typeseizures, often in addition to other generalised and/or focal seizures.The participants in the study were part of an expanded accesscompassionate use program for CBD.

The epileptic syndromes that these patients suffered from were asfollows: Myoclonic Absence Epilepsy; Doose Syndrome; and epilepsy ofunknown cause.

All patients entered a baseline period of 4 weeks whenparents/caregivers kept prospective seizure diaries, noting allcountable seizure types.

The patients then received a highly purified CBD extract (greater than98% CBD w/w) in sesame oil, of known and constant composition, at a doseof 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED)regimen.

The daily dose was gradually increased by 2 to 5 mg/kg increments untilintolerance occurred or a maximum dose of 25 mg/kg/day was achieved.

Patients were seen at regular intervals of 2-4 weeks. Laboratory testingfor hematologic, liver, kidney function, and concomitant AED levels wasperformed at baseline, and after every 4 weeks of CBD therapy.

The patients on the study were all taking at least one concomitant AED.These included clobazam, clonazepam, clorazepate, diazepam,ethosuximide, ketogenic diet, lacosamide, lamotrigine, levetiracetam,lorazepam, midazolam, and valproic acid.

Results

Of the 10 children and young adult patients who received treatment withCBD, there were 8 patients who received treatment for at least 12 weeksof treatment all of whom suffered from myoclonic absence type seizures.

A summary of the 50% responders, based on 12 weeks of treatment aresummarized in Table 8 below.

TABLE 8 Summary of 50% responders after 12 weeks of treatment Myoclonicabsence seizures Total seizures (n = 10) (n = 137) >50% reduction in 75%(n = 6) 46% (n = 63) seizures <50% reduction in 25% (n = 2) 54% (n = 74)seizures

Table 8 shows that after 3 months of therapy, a remarkable 75% ofpatients had an equal to or greater than >50% reduction in absenceseizures, these data infer that the CBD is very effective at reducingthis type of seizure.

Conclusions

These data indicate that CBD significantly reduces the number ofmyoclonic absence seizures in a high proportion of patients that do notrespond well to existing AED.

It was surprising that in this group of patients which aretreatment-resistant such a high number were able to gain an effect. Thefact that nearly three quarters of the patients (75%) benefitted from atleast a fifty percent reduction in the number of myoclonic absenceseizures that they suffered from was remarkable.

REFERENCES

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1. A method of treating epilepsy comprising administering cannabidiol(CBD) to a subject, wherein the epilepsy is characterised by absenceseizures.
 2. The method according to claim 1, wherein the absenceseizures are myoclonic absence seizures.
 3. The method according toclaim 1, wherein the epilepsy is treatment-resistant epilepsy (TRE). 4.The method according to claim 1, wherein the CBD is administered incombination with one or more concomitant anti-epileptic drugs (AED). 5.The method according to claim 1, wherein the absence seizures to betreated are in subjects diagnosed with: Lennox-Gastaut Syndrome;Myoclonic Absence Epilepsy; Tuberous Sclerosis Complex; Dravet Syndrome;Doose Syndrome; Jeavons Syndrome; CDKL5; Dup15q; Neuronal ceroidlipofuscinoses (NCL) and brain abnormalities.
 6. The method according toclaim 5, wherein the subject is diagnosed with Lennox-Gastaut Syndrome.7. The method according to claim 5, wherein the subject is diagnosedwith Dravet Syndrome.
 8. The method according to claim 5, wherein thesubject is diagnosed with Myoclonic Absence Epilepsy.
 9. The methodaccording to claim 1, wherein the CBD is a highly purified extract ofcannabis which comprises at least 98% (w/w) CBD.
 10. The methodaccording to claim 9, wherein the extract comprises less than 0.15% THC.11. The method according to claim 9, wherein the extract furthercomprises up to 1% CBDV.
 12. The method according to claim 1, where inthe CBD is present as a synthetic compound.
 13. The method according toclaim 4, wherein the one or more AED is selected from the groupconsisting of: clobazam, clonazepam, clorazepate, desmethylclobazam,diazepam, ethosuximide, felbamate, gabapentin, ketogenic diet,lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam,N-desmethylclobazam, nordiazepam, phenytoin, stiripentol, topiramate,trazodone, vagus nerve stimulation, valproic acid, vigabatrin, andzonisamide.
 14. The method according to claim 13, wherein the one ormore AED is selected from the group consisting of: sodium valproate;lamotrigine; ethosuximide; clobazam; and clonazepam.
 15. The methodaccording to claim 4, wherein the number of different anti-epilepticdrugs that are used in combination with the CBD is reduced.
 16. Themethod according to claim 4, wherein the dose of anti-epileptic drugsthat are used in combination with the CBD is reduced.
 17. The methodaccording to claim 1, wherein the dose of CBD is greater than 5mg/kg/day.
 18. The method according to claim 1, wherein the epilepsy ischildhood epilepsy.
 19. A method of treating epilepsy characterised byabsence seizures comprising administering cannabidiol (CBD), a solvent,a co-solvent, a sweetener, and a flavouring to a subject.
 20. The methodaccording to claim 19, wherein the solvent is sesame oil.
 21. The methodaccording to claim 19, wherein the co-solvent is ethanol.
 22. The methodaccording to claim 19, wherein the sweetener is sucralose.
 23. Themethod according to claim 19, wherein the flavouring is strawberryflavour.
 24. The method according to claim 19, wherein the CBD ispresent at a concentration of between 25/mg/ml and 100 mg/ml.
 25. Themethod according to claim 19, wherein cannabidiol (CBD) is administeredat a concentration of between 25 to 100 mg/ml, ethanol at aconcentration of 79 mg/ml, sucralose at a concentration of 0.5 mg/ml,strawberry flavouring at a concentration of 0.2 mg/ml and sesame q.s. to1.0 ml.